Somatic and hereditary variations in gene copy number can lead to profound abnormalities at the cellular and organismal levels. In human cancer, chromosomal changes, including deletion of tumor suppressor genes and amplification of oncogenes, are hallmarks of neoplasia (1). Single copy changes in specific chromosomes or smaller regions can result in a number of developmental disorders, including Down, Prader Willi, Angelman, and cri du chat syndromes (2). Current methods for analysis of cellular genetic content include comparative genomic hybridization (CGH) (3), representational difference analysis (4), spectral karyotyping/M-FISH (5, 6), microarrays (7-10), and traditional cytogenetics. Such techniques have aided in the identification of genetic aberrations in human malignancies and other diseases (11-14). However, methods employing metaphase chromosomes have a limited mapping resolution (˜20 Mb) (15) and therefore cannot be used to detect smaller alterations. Recent implementation of comparative genomic hybridization to microarrays containing genomic or transcript DNA sequences provide improved resolution, but are currently limited by the number of sequences that can be assessed (16) or by the difficulty of detecting certain alterations (9). There is a continuing need in the art for methods of analyzing and comparing genomes.